Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N-alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.


■ INTRODUCTION
Chiral vicinal diamines are extremely valuable and important motifs in organic chemistry that are exploited by both nature and the pharmaceutical industry for their biological activities, 1,2 and in stereoselective organic synthesis as powerful chiral inducers through application as organocatalysts, 3 chiral ligands 4 for transition metal catalyzed reactions, and as chiral auxiliaries. 5 For example, a variety of biologically active pharmaceuticals and natural products are given in Figure 1 possessing either the chiral 1,2-diamino-fragment or its corresponding urea form. 2 Representative therapeutics being developed for the treatment of important human diseases include antibiotics (penicillin, 2e jogyamycin 2j ), anticancer compounds (cisplatin derivatives, 6 LP99 2c ), HIV protease inhibitors (NBD-11021 2d ), NK 1 -antagonists 7 (CP-99,994; 2a Sch425078 2g ) for central-nervous-system (CNS) related diseases and rheumatoid arthritis, and influenza (tamiflu). 2b Due to the biological and synthetic value of chiral 1,2diamines, stereoselective methods for their preparation are an important endeavor in organic chemistry. 1a,c,d,8 Potential synthetic options to access the chiral vicinal diamine moiety can be envisioned to occur either by formation of the two C− N bonds starting from unsaturated hydrocarbons (2, Scheme 1A) or through direct C−C bond formation between C1 and C2 of the 1,2-diamine from two N-substituted reagents (Scheme 1B). 1a,c,d,8 Using a C−N bond forming approach (Scheme 1A), diamination may be achieved by forming both C−N bonds at the same time, 8,9 or sequentially through either aziridination 10 followed by ring-opening with an amine nucleophile 1a,c,d,11 or through aminohydroxylation 12 followed by alcohol activation and amine substitution. 1a−d While direct catalytic 1,2-diamination of 2 represents an ideal strategy for diamine synthesis, the amino-groups added across the π-system are typically identical leading to the formation of diamines with identical substituents (i.e., R 3 = R 4 in 1), 8,9 and a recent approach employing electrochemistry 9b suffers from potentially forming high-energy/explosive diazocompounds 13 en route to the desired diamines. Additionally, the aziridination/ringopening strategy can suffer from poor stereoselectivity in the aziridination step and regiochemistry issues in the subsequent opening step, while the aminohydroxylation route requires regiocontrol in the aminohydroxylation step followed by additional transformations to convert 4 to the desired diamine. Alternatively, synthesis of 1 through C−C bond formation can be achieved through aza-pinacol coupling of two imines, 14 nitro-Mannich, 15 or glycine-Mannich 16 reactions (Scheme 1B). Typical aza-pinacol coupling protocols only afford symmetrical diamines through homocoupling of a single imine; however, recent photoredox strategies 14h−l enabling the generation of αaminoradicals 17 from amines have enabled cross-selective coupling of imines and N-methylamines. 14j−l Furthermore, nucleophilic additions to imines using α-aminoanion deriva-tives 18 from nitroalkanes (7) 15 or protected glycines (8) 16 offer another entry into the diamine core 1.
In regards to chiral amine synthesis, asymmetric allylation of imines using allyl organometallic nucleophiles (10) by direct addition or through catalyst control has been an area of intense research in organic chemistry (Scheme 2). 19 The chiral allylamine products (11) are highly valuable in the context of the synthesis of complex amine-containing organic compounds because of the high versatility of the olefin functional group present within 11. Substituted allylorganometallic reagents (e.g., 12) allow for increased molecular complexity by introducing two stereocenters in the allyl addition reaction (e.g., 13, Scheme 2B). Therefore, we envisioned that use of an amino-substituted allyl reagent 12 in addition reactions with imine electrophiles would be a powerful strategy to prepare 1,2-diamines (13) with differential substitution patterns on nitrogen and containing an olefin motif for further functional group manipulations. Surprisingly, only a single example of such a strategy for the preparation of 1,2-diamines has been reported, which employs a lithiated derivative of 12 (M = Li) with chiral tert-butanesulfinimide derived aldimines affording products in moderate yields with mixtures of branched and linear allylation products. 20 In contrast, amino-substituted allyl reagents 12 have been used in reactions employing carbonyl electrophiles to provide 1,2aminoalcohols (16). 21

Scheme 1. Synthetic Strategies toward the Synthesis of 1,2-Diamines
The Journal of Organic Chemistry pubs.acs.org/joc Article our own lab 23 have developed reductive coupling 24,25 procedures for the catalytic generation of amino-substituted allyl reagents 12 and have studied their reactions with carbonyl electrophiles (Scheme 2C). These techniques represent orthogonal methodologies whereby the Krische 22a system employs a chiral Ir-catalyst and processes aldehyde electrophiles using an achiral allenamide (15), while our work utilizes a Cu-catalyst and a chiral allenamide (15a) for reactions using ketone electrophiles. 23 Based on our success in the stereoselective Cu-catalyzed reductive coupling of ketones and chiral allenamides to afford branched chiral 1,2-aminoalcohols 16 23a or the corresponding linear products, 23b and the lack of literature data for imine allylation reaction utilizing aminosubstituted allylic nucleophiles, we began to investigate the reaction of allenamide 15a with imine electrophiles 9 for the stereoselective synthesis of chiral 1,2-diamine synthons 17 (Scheme 2D). The results of these studies leading to the identification of a practical and highly stereoselective synthesis of diamine synthons 17 using Cu-catalyzed reductive coupling are disclosed herein.
■ RESULTS AND DISCUSSION Reaction Optimization. To investigate the proposed Cucatalyzed reductive coupling of imines and allenamides, initial studies examined the ligand effect when employing DMBprotected imine 9a with chiral allenamide 15a in the reaction ( Table 1). The phenyl-derived Evans oxazolidinone of allenamide 15a was specifically targeted due to its low-cost and high-availability, 26 and because it allows for more deprotection options of the desired diamine products over other alkyl-substituted oxazolidinones (i.e., hydrogenolysis). The DMB-group of the aldimine was employed due to its acid lability to allow for chemoselective differentiation of the two amine protecting groups in the final products (18a/19a). Gratifyingly, a variety of phosphine ligands (entries 1−7) afforded urea product 19a presumably resulting from migration of the carbamate carbonyl (Scheme 3), whereas an Nheterocyclic carbene (NHC) ligand provided poor conversion (entry 8). In all cases, a single diastereomer of product was obtained as determined by 1  unpurified reaction mixture. Notably, the bidentate phosphine dcpe that has been utilized previously in Cu-catalyzed reductive coupling of C-substituted allenes and imines 25c afforded only a moderate yield with a substantial amount of unreacted imine (20%, entry 1). Monodentate phosphine ligands (entries 2−7) worked well with the exception of sterically demanding ligands that afforded poor conversion of the imine (entries 3, 4). Ultimately, the use of PCy 3 as ligand afforded the highest yield of 19a in the reaction (entry 2). Use of solvents other than toluene in the reaction (entries 9−12) offered no improvements. Finally, addition of 2 equiv of t-BuOH to the reaction led to the exclusive formation of 18a in excellent yield and diastereoselectivity. An initial working hypothesis to understand the difference in product selectivity between the formation of urea 19a in the absence of t-BuOH versus the exclusive formation of diaminoderivative 18a when t-BuOH was used as an additive is given in Scheme 3. Regioselective hydrocupration of allenamide 15a by the LCuH 23,25c catalyst 20 initially is expected to afford substituted linear allylcopper reagent 21 that may undergo E/Z isomerization through σ−π−σ equilibration prior to reaction with the imine electrophile. Then, diastereoselective reaction of intermediate 21 with imine 9a provides Cu-amide intermediate 22. To afford product 18a from 22, direct silylation of the amine by the silane must occur to regenerate the LCuH catalyst 20; however, this step is expected to be slow due to the weak strength of the N−Si bond (BDE ≈ 104 kcal/ mol). 27 Due to the strong basicity of the N-anion in 22, intramolecular attack of the oxazolidinone carbonyl may occur competitively to provide 23 containing an O−Cu bond that should more easily silylate due to the high bond strength of the O−Si bond (BDE ≈ 190 kcal/mol) 28 affording urea 24 and regenerating the LCuH catalyst (20). Alternatively, when t-BuOH is present, protonation of the Cu−N bond of 22 by t-BuOH to afford product 18a directly and generate LCuO t Bu is thermodynamically favorable based on the pK a values for a secondary amine (pyrrolidine: ∼44) 29 vs t-BuOH (32) and supported by DFT calculations (vide infra). 30 The LCu-O t Bu intermediate can then undergo silylation to regenerate the LCuH catalyst 20. The role of alcohol additives to facilitate catalyst turnover by protonation of Cu−N intermediates has been documented previously. 25c,31 Sterically hindered alcohols such as t-BuOH have been shown to be preferred since the rate of competitive protonation of the Cu−H catalyst is reduced with bulky alcohols. 31 Next, the substrate scope of the Cu-catalyzed reductive coupling reaction using t-BuOH as additive to provide branched diamino-derived products 18 was examined (Scheme 4). In all cases, a single diastereomer (the (S,S,S)diastereomer) of product was obtained as determined by analysis of the unpurified reaction mixture by 1 H NMR spectroscopy. In general, a wide variety of imines could be employed in the reaction in good to excellent yields. Electrondeficient (18a − 18k) and electron-rich (18l−18o) aryl groups both performed well in the reaction. Heterocyclic imines (18k, 18s−18u) and C-substituted arenes (18p−18r) were also well tolerated. Finally, a sterically demanding imine (18m) or a m-NO 2 Ph group (18i) required heating at 65°C to afford good reactivity. Use of an aliphatic aldimine (i.e., Ar 1 = Me) did not provide any desired products.
Initial analysis of the substrate scope for the urea-forming Cu-catalyzed reductive coupling reaction employing DMBsubstituted imines in the absence of t-BuOH proved to be less general than the analogous reaction conducted with t-BuOH as the additive. In these problematic cases, a poor yield of desired product was obtained even at 65°C; however, the imine remained while the allenamide had been consumed. As a result, the effect of the N-substituent of the imine electrophile was examined to improve the efficiency of the reaction to the desired product ( Table 2). As an example, the 2-naphthyl N-DMB-imine (9pa) afforded a poor yield in the desired reaction (entry 1). A strong influence on reactivity and the electronic character of the aryl group (Ar 2 ) of the imine was found (entries 1−5). Use of an electron-poor aryl group (entry 5) afforded the best reaction yield; however, a simple benzyl group also provided good reactivity (entry 3). As a result, for problematic DMB-derived imines, the reactivity can be improved by utilizing PMB, Bn, or p-CF 3 -benzyl as the Nsubstituent on the aldimine.
Based on the results from Table 2, the substrate scope for the urea-forming Cu-catalyzed reductive coupling reaction in the absence of t-BuOH was investigated using this new knowledge (Table 3). DMB-substituted imines could be employed in good yields affording single diastereomers of product at room temperature when Ar 1 was a simple phenyl group (19b), heterocyclic (19k, 19s, 19t), or substituted at the para-position with an electron-donating group (19l, 19n) or an electron-withdrawing group (19a). However, reactions employing imines containing halogenated arenes or more sterically demanding aryl groups were not successful utilizing the N-DMB derived imine and instead required heating and the use of either an N-Bn or an N-CH 2 -p-CF 3 Ph group on the aldimine (see 19de, 19ee, 19j and 19m, 19pe, respectively).
Stereochemical assignment of the products obtained in the Cu-catalyzed reductive coupling reaction as the (S,S,S)diastereomer was determined unequivocally by X-ray crystallography (Scheme 5). While the branched products 18 were typically noncrystalline, formation of the HCl-salt of 18c afforded crystalline material whose structure was determined by single-crystal Xray analysis. Furthermore, conversion of products 18 to the urea 19 could also be achieved after  isolation of 18 by subsequent treatment with n-BuLi (e.g., 18a → 19a). The urea product obtained from this sequence was identical to the material made from the reductive coupling reaction performed in the absence of t-BuOH by NMR spectroscopy confirming that the same stereoisomer of product was formed in both reductive coupling processes (i.e., with or without t-BuOH as additive). The synthetic utility of the reaction products obtained in the allenamide/imine reductive coupling reaction is highlighted in Scheme 6. The phenethyl group of urea 19a derived from the Evans oxazolidinone of the allenamide starting material could be cleaved in a three-step sequence consisting of alcohol activation (MsCl), base induced elimination, and enamide hydrolysis with aqueous acid to provide urea 25 in good overall yield without isolation of intermediates. Furthermore, synthon 27 is a viable intermediate to access chiral aminopiperidine 28 for the preparation of the potent NK-1 inhibitor compounds CP-99,994 and CP-122,721, 2a,7 which could easily be accessed from reductive coupling product 18c (Scheme 6). The Cucatalyzed reductive coupling was scaled to 1.0 g without the need for an inert atmosphere glovebox by performing the reaction on the "benchtop" using standard Schlenk techniques and preparing the (PCy 3 )Cu-catalyst by adding the PCy 3 as a 20 wt % solution in toluene that is commercially available. 32 The catalyst loading could be reduced to 2.0 mol % Cu providing 18c in good yield and excellent diastereocontrol in only 2 h of reaction time. Considering the low cost and high availability of the Cu-precatalyst, 32 the ligand employed (PCy 3 ), 32 and the chiral allenamide 15a, 26 along with the high catalytic activity of this system (2 mol % catalyst loading), the current method represents a highly practical and scalable method for the synthesis of diamino-synthons 18/19. Allylation of 18c was then carried out using allyl bromide, followed by ring-closing metathesis with the Hoveyda−Grubbs second generation catalyst to provide access to compound 27 as an orthogonally protected aminopiperidine derivative as a single stereoisomer.
Mechanistic Modeling by DFT Analysis. To shed light onto the mechanism and origin of diastereoselectivity, we used dispersion-corrected DFT calculations (see Supporting Information for details). Specifically, we performed extensive conformational analysis on all intermediates and transition states using the B3LYP-D3 functional and a def2-SVP basis set 33 with toluene as the solvent using the CPCM solvation model 34 as implemented in Gaussian16. Further, to refine the energetics and compare methods, single-point calculations using the M06-L functional, 35 as well as a larger basis set (def2-TZVPP) with B3LYP-D3, which yielded similar energetic profiles, were subsequently performed. For simplicity, only B3LYP-D3/def2-SVP optimization energetics will be discussed in the text. Structures were visualized using CYLview Version 1.0.561. 36 As shown in Figure 2, initial investigations were conducted by first analyzing the hydrocupration of allenamide 15a with (PCy 3 )CuH as catalyst. Following coordination of the copper and allenamide π-bond, the energetically favored hydrocupration proceeds via TS−I-II (barrier of 10.4 kcal/mol with respect to separated 15a and LCuH structures) to form the branched allylcopper species II. Presumably this transition state benefits from lack of steric hindrance between the ligand and the chiral auxiliary, which were present in the alternative transition states. Specifically, alternate hydrocupration transition states leading to linear allylcopper species (TS−I-III cis and TS−I-III trans) were found to be much higher in energy by ∼3 kcal/mol for TS−I-III trans and by >7 kcal/mol for all other pathways and were therefore not productive.
In turn, the branched allylcopper intermediate is expected to undergo isomerization to linear allylcopper species by σ−π−σ isomerization. Recently, Buchwald and co-workers reported branched-linear allylcopper isomerizations for a system with a bidentate phosphine ligand 25c as well as with a CuH-catalyzed allylation of ketones and dienes. 37 In our case, it was calculated that the branched allylcopper intermediate II can readily isomerize (barrier of only 6.9 and 10.0 kcal/mol via TS−II-III cis or TS−II-III trans, respectively) to form the nearly isoenergetic cis or trans linear allylcopper intermediates (III cis and III trans). Intermediate III cis was slightly favorable compared to intermediate III trans (by 0.6 kcal/mol), as was the cis isomerization transition state (TS−I-III cis was favored by 3.1 kcal/mol), presumably due to coordination between the oxazolidinone and the copper (Cu−O bond distance = 2.37 The Journal of Organic Chemistry pubs.acs.org/joc Article Å). However, upon coordination of the imine to the copper, the trans conformation (III′ trans) becomes significantly more favored (as seen in Figure 3), likely due to unfavorable steric hindrance between the imine and the oxazolidinone in the III′ cis conformation (see Supporting Information for further details). Next, we focused on the key C−C bond formation steps. As shown in Figure 3, after performing extensive conformational analysis on the subsequent diastereomeric C−C bond forming transition states with the allylcopper intermediates and the imine substrate (see Supporting Information for details), the most favorable pathway for diastereoselective C−C bond formation was identified to proceed from the trans linear intermediate Notably, all C−C bond formation steps f rom III′trans are reversible, as the branched addition products IV (S,S,S) and IV (R,R,S) were each uphill in energy (by ∼2 kcal/mol and ∼6 kcal/mol respectively), which can have implications for rational catalyst and reaction design (vide infra).
To gain insights into the origin of diastereoselectivity, we performed distortion−interaction and NCI analysis ( Figure 4). Overall, comparing the structures of the lowest energy competing diastereomeric transition states TS-III′-IV trans (S,S,S) and TS-III′-IV trans (R,R,S) reveals that the structures of these transition states were remarkably similar, with key C− C and C−Cu bond distances differing by no more than 0.05 Å. However, the orientation of the chiral auxiliary is different, as the TS-III′-IV trans (S,S,S) transition state has the oxazolidinone moiety of the enamide group of the substituted Cu(allyl) ligand in an s-trans conformation while the TS-III′-IV trans (R,R,S) has this group in an s-cis conformation that, as shown in Figure 5, leads to a 2.2 kcal/mol energy destabilization. Furthermore, the ground state structures of chiral oxazolidinone-derived enamides are known to favor an s- trans conformation. 38 In addition, distortion−interaction analysis 39 (Figure 4a) showed that the distortion energy of the TS-III′-IV trans (S,S,S) transition state was higher than that of the corresponding TS-III′-IV trans (R,R,S) transition state (by 3.9 kcal/mol). However, the (S,S,S) system benefited from much stronger interaction energy (by 8.5 kcal/mol). Overall, this favorable interaction between the imine and allylcopper makes the TS-III′-IV trans (S,S,S) the favorable diastereomeric transition state. Finally, noncovalent interaction (NCI) analysis (performed using Multiwfn 40 software and visualized using VMD 41 software) further supports the presence of favorable interactions in the TS-III′-IV trans (S,S,S) transition state ( Figure 4b). Specifically, in both transition states, there appeared to be favorable C−H···π interactions between the ligand and the benzyl group of the imine (highlighted inside the blue circle). However, comparing the areas in red circles, the TS-III′-IV trans (S,S,S) system had stronger noncovalent interactions between the oxazolidinone group and the phenyl ring on the imine. This suggests that noncovalent interactions (i.e., between the oxazolidinone moiety and the protecting group) are critical for control of diastereoselectivity. Taken together, these results suggest that both the conformational preference for the s-trans geometry about the N-enamide group of the substituted Cu(allyl) ligand and favorable noncovalent interactions between the oxazolidinone group and the imine are the major contributing factors for diastereocontrol in these reactions.
Following C−C bond formation, intermediate IV serves as a fork between two reaction pathways depending on whether or not there is t-BuOH present (as supported by experiments; vide supra). Specifically, in the presence of t-BuOH, the alcohol can act as a proton source to protonate the Cu−N bond and yield branched product 18, while the alkoxide binds to the copper. From this, the silane reagent can exchange hydride for the alkoxide group, reforming the catalyst. While this protonation of the amine moiety and concomitant release of the t-BuO-CuL was calculated to be initially energetically unfavorable (uphill by ∼4 kcal/mol), the exchange of hydride for the alkoxide was thermodynamically favorable (downhill by ∼10 kcal/mol), rendering this overall process energetically feasible. In the absence of t-BuOH, a thermodynamically favorable rearrangement of intermediate IV can yield the Cualkoxide urea intermediate V (∼7 kcal/mol exergonic), which can then readily undergo transmetalation with silane to reform the LCuH catalyst and furnish the silylated product of urea 19. This mechanistic model is consistent with experimental findings that the presence of t-BuOH has a profound effect on the product selectivity (but not diastereoselectivity) of the reaction toward either of the products (vide supra).
As previously noted, computational modeling of the imine addition predicts this step should be reversible. This phenomenon has important impacts for future developments of catalyst controlled enantioselective reactions utilizing a chiral catalyst in conjunction with an achiral allenamide. In this regard, reaction of achiral allenamide 15b with imine 9a using (S,S)-Ph-BPE as a chiral ligand was examined with and without t-BuOH as the additive (Scheme 7). Again, branched product 29 was formed as a single diastereomer when t-BuOH was present in the reaction, and urea 30 was formed as a single diastereomer in the absence of t-BuOH. Separate conversion of 29 to 30 using n-BuLi confirmed that the same relative stereochemistry was formed in both reactions. Importantly, 29 and 30 were formed in different enantiopurities (57:43 vs 80:20 er, respectively), supporting a reversible imine addition step in these reactions. For example, if imine addition were irreversible, reaction of 15b with a chiral catalyst to afford the analogous intermediate to 22 (Scheme 3) must be enantiodetermining and requires that urea product 30 formed from rearrangement of the intermediate 22 derivative to have identical enantiopurity to that of 29. However, when a chiral ligand is employed, rearrangement of the two enantiomers of intermediate 22 may occur at different rates because the transition states will be diastereomeric due to the chirality on the ligand. Therefore, the carbamate migration step may also be enantiodetermining if the imine addition step becomes reversible enabling different enantiomeric ratios to be obtained for a 29-selective vs a 30-selective process as was observed.

■ CONCLUSION
In conclusion, a highly stereoselective method for the reductive coupling of imines with a chiral allenamide was developed as a convenient strategy for the asymmetric synthesis of valuable 1,2-diamino synthons. The method employs readily available and cost-effective starting materials 26 and catalyst (Cu(OAc) 2 / PCy 3 ) 32 and can be performed on the "bench-top" using standard Schlenk techniques without issues. Use of tert-butanol as an additive was shown to aid in the amine release and catalyst regeneration to avoid the formation of urea products that are exclusively obtained in the absence of this additive. The oxazolidinone moiety of the final products could be removed chemoselectively without disruption of the pendant terminal alkene, and an orthogonally protected chiral aminopiperidine derivative en route to important biologically active pharmaceuticals was demonstrated. Finally, mechanistic investigations by density functional theory calculations identified the mechanism for stereoselection in these processes as determined from the relative transition state barriers of Nsubstituted allylcopper complexes to the imine electrophile. This C−C bond forming addition step was shown to be reversible by calculation and was experimentally supported by the catalytic asymmetric reaction of a chiral catalyst with an achiral allenamide. These mechanistic insights are important for the development of future asymmetric catalyst-controlled procedures and are currently under further investigation in these laboratories.

■ EXPERIMENTAL SECTION
General. 1 H NMR spectra were recorded on Bruker 600 MHz spectrometers. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl 3 : 7.26 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = hextet, hept = heptet, br = broad, m = multiplet), and coupling constants (Hz). 13 C NMR spectra were recorded on a Bruker 600 MHz (151 MHz) instrument with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard (CDCl 3 : 77.0 ppm). Liquid chromatography was performed using forced flow (flash chromatography) on silica gel purchased from Silicycle. Thin layer chromatography (TLC) was performed on glass-backed 250 μm silica gel F 254 plates purchased from Silicycle. Visualization was achieved by using UV light, a 10% solution of phosphomolybdic acid in EtOH, or potassium permanganate in water followed by heating. HRMS was collected using a Jeol AccuTOF-DART mass spectrometer using DART source ionization. All reactions were conducted in oven or flame-dried glassware under an inert atmosphere of nitrogen or argon with magnetic stirring unless otherwise noted. Solvents were obtained from VWR as HPLC grade and transferred to septa sealed bottles, degassed by argon sparge, and analyzed by Karl Fischer titration to ensure water content was ≤600 ppm. Me(MeO) 2 SiH was purchased from Alfa Aesar and used as received. Allenamides 15 were prepared in one step as described in the literature. 26 Aldehydes were purchased from Sigma-Aldrich, Combi-Blocks, TCI America, Alfa Aesar, or Oakwood Chemicals and used as received. Tricyclohexylphosphine and Cu(OAc) 2 were purchased from the Strem Chemical Company and used as received. All other materials were purchased from VWR, Sigma-Aldrich, Combi-Blocks, or Alfa Aesar and used as received. Imines 9a, 42 9b, 43 9c, 44 9ee, 45 9h, 46 9i, 47 9j, 48 9l, 45 9m, 47 9pb, 49 9pc, 50 and 9u 45 were synthesized as described in the literature.
General Procedure A for the Synthesis of Imines. A 25 mL round-bottom flask equipped with a magnetic stirring bar was charged with aldehyde (6.0 mmol, 1.0 equiv) and dichloromethane (8 mL). Anhydrous magnesium sulfate was added to this solution while stirring followed by 2,4-dimethoxy benzylamine (6.0 mmol, 1.0 equiv) dropwise. The reaction mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. After the reaction is complete the crude reaction mixture was filtered through Celite to remove magnesium sulfate. The filtrate was concentrated in vacuo to yield the pure imine, which was stored under nitrogen in the fridge.
The Journal of Organic Chemistry pubs.acs.org/joc Article Allenamide 15a (96.6 mg, 480 μmol) followed by imine (400 μmol) was then charged, and the vial was sealed with a crimp-cap septum and removed from the glovebox. Dimethoxymethylsilane (0.099 mL, 2 equiv) was then charged to the reaction mixture (Caution:dimethoxymethylsilane should be handled in a well-ventilated fume hood because it is known to cause blindness. Syringes were quenched with 2 M NaOH, gas evolution! prior to disposal). The mixture was then stirred at rt for 24 h. The reaction was quenched by addition of 200 mg of NH 4 F and 2.5 mL of MeOH followed by agitation at rt for 30 min. A 10 mL volume of 5% NaHCO 3 was then added to the mixture followed by extraction with DCM (2 × 5 mL). The combined organics were dried with Na 2 SO 4 , filtered, and concentrated in vacuo. Crude product was purified by flash chromatography on silica gel to afford the desired product 19.  (4S,5S)-4-(4-Fluorophenyl)-1-((S)-2-hydroxy-1-phenylethyl)-3-(4-(trifluoromethyl)benzyl)-5-vinylimidazolidin-2-one (19ee). The reaction was set up according to general procedure C and stirred at 65°C for 24 h. The product was purified by silica gel chromatography (4S,5S)-1-(2,4-Dimethoxybenzyl)-3-((S)-2-hydroxy-1-phenylethyl)-5-(4-methoxyphenyl)-4-vinylimidazolidin-2-one (19l). According to General Procedure C, the product was purified by silica gel chromatography (10% E.A. in DCM) to provide 184 mg (94%) of 19l as a colorless foam as a single diastereomer. R f = 0.29 (50% EtOAc/hexanes). 1   (4S,5S)-1-(2,4-Dimethoxybenzyl)-5-(furan-2-yl)-3-((S)-2-hydroxy-1-phenylethyl)-4-vinylimidazolidin-2-one (19s). According to General Procedure C, the product was purified by silica gel chromatography (5% E.A. in DCM) to provide 149 mg (83%) of 19s as a colorless foam as a single diastereomer. R f = 0.28 (50% EtOAc/hexanes). 1  Synthesis of 29 from Achiral Allenamide 15b. To a 20 mL crimp cap vial with a stir bar in an Ar filled glovebox were charged Cu(OAc) 2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol) followed by toluene (2.5 mL) and tert-butanol (26.3 μL, 275 μmol). The mixture was stirred for 5 min. Allenamide 15b (37.5 mg, 300 μmol) followed by imine 9a (250 μmol) was then charged, and the vial was sealed with a crimp-cap septum and removed from the glovebox. Dimethoxymethylsilane (0.061 mL, 2 equiv) was charged to the reaction mixture, and the reaction mixture was stirred at rt for 24 h. The reaction was quenched by addition of 100 mg of NH 4 F and 1.5 mL of MeOH followed by agitation at rt for 30 min. A 5 mL volume of 5% NaHCO 3 was then added to the mixture followed by extraction with DCM (2 × 3 mL). The combined organics were dried with Na 2 SO 4 , filtered, and concentrated in vacuo.  Synthesis of 30 from Achiral Allenamide 15b. To a 20 mL crimp cap vial with a stir bar in an Ar filled glovebox were charged Cu(OAc) 2 (1.8 mg, 10 μmol) and Ph-BPE (5.1 mg, 10 μmol) followed by toluene (0.5 mL). The mixture was stirred for 5 min. Allenamide 15b (37.5 mg, 300 μmol) followed by imine 9a (250 μmol) was then charged, and the vial was sealed with a crimp-cap septum and removed from the glovebox. Dimethoxymethylsilane (0.061 mL, 2 equiv) was then charged to the reaction mixture. The mixture was then stirred at rt for 24 h. The reaction was quenched by addition of 100 mg of NH 4 F and 1.5 mL of MeOH followed by agitation at rt for 30 min. A 5 mL volume of 5% NaHCO 3 was then added to the mixture followed by extraction with DCM (2 × 3 mL). The combined organics were dried with Na 2 SO 4 , filtered, and concentrated in vacuo. Crude product was purified by flash chromatography on silica gel (50% EtOAc/hexanes) to afford 68 mg (60%) of 30 as a colorless liquid and as an 80:20 mixture of enantiomers as determined via chiral HPLC analysis (Chiracel AD-3 90:10 heptane/isopropanol 1.00 mL/min, 220 nm). R f = 0.28 (50% EtOAc/hexanes). 1  Synthesis of 18c on 1.0 g Scale. To a 20 mL crimp cap vial was charged Cu(OAc) 2 (16.1 mg, 88.9 μmol), and the vial was sealed with a crimp-cap septum. The vial was evacuated and backfilled with nitrogen 3 times and then charged with toluene (5 mL), 20% PCy 3 solution in toluene (194 μL, 111 μmol), and tert-butanol (0.85 mL, 8.89 mmol), and the mixture was allowed to stir at rt for 10 min until all the Cu(OAc) 2 dissolved. A 50 mL two-neck round-bottom flask was then charged with imine 9c (1.0 g, 4.44 mmol) and allene 15a (1.07 g, 5.33 mmol), and the flask was evacuated and backfilled with nitrogen 3 times. The flask was then charged with toluene (5 mL). The imine/allene flask was then charged with the catalyst solution. Dimethoxymethyl silane (1.1 mL, 8.89 mmol) was charged to the reaction mixture (caution:dimethoxymethylsilane should be handled in a well-ventilated f ume hood because it is known to cause blindness. Syringes were quenched with 2 M NaOH, gas evolution! prior to disposal), and the reaction was allowed to stir at rt for 2 h. A 50 mL round-bottom flask was charged with NH 4 F (2 g) and MeOH (20 mL), and the reaction mixture was transferred via pipet to this flask and allowed to stir at rt for 30 min. The volatiles were concentrated in vacuo, and 50 mL of 5% NaHCO 3 solution were added to the flask. The mixture was extracted with CH 2 Cl 2 (2 × 20 mL), and the combined organics were dried over Na 2 SO 4 and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% EtOAc/DCM) to afford 1.655 g (91%) of 18c as a white solid as a single diastereomer.
Synthesis of 25. To a solution of 207.5 mg (393 μmol) of 19a in 2 mL of CH 2 Cl 2 at 0°C were charged 66 μL (473 μmol) of triethylamine followed by dropwise addition of 30.5 μL (393 μmol) of MsCl. The mixture was stirred for 30 min at 0°C, and then 4 mL of 10% NH 4 Cl were added. The mixture was extracted with CH 2 Cl 2 (3 × 5 mL). The combined organics were dried with anhydrous Na 2 SO 4 and filtered, and the volatiles were removed in vacuo. The crude residue was then dissolved in 2 mL of THF and cooled to 0°C. A 1.0 M concentration of potassium tert-butoxide (433 μL, 433 μmol) in THF was then added, and the mixture was warmed to room temperature and stirred for 30 min. To the mixture was added 5 mL of 10% brine followed by extraction with CH 2 Cl 2 (3 × 5 mL). The combined organics were dried with anhydrous Na 2 SO 4 and filtered, and the volatiles were removed in vacuo. The crude residue was then dissolved in 4 mL of THF in a crimp cap vial. To the solution were then added 788 μL (3.94 mmol) of 5.0 M aqueous H 2 SO 4 . The vial was purged with argon, sealed, and immersed in an oil bath at 50°C. After 3 h the reaction mixture was cooled to room temperature, and 15 mL of saturated aqueous NaHCO 3 were added. The mixture was extracted with CH 2 Cl 2 (3 × 5 mL). The combined organics were dried with anhydrous Na 2 SO 4 and filtered, and the volatiles were removed in vacuo. The crude residue was purified by flash chromatography (20% EtOAc/DCM) to afford 112 mg (70%) of 25 as a colorless foam. R f = 0.22 (50% EtOAc/hexanes). 1  Synthesis of 19a from 18a. To a solution of 100 mg (190 μmol) of 18a in 1.0 mL of THF at −10°C were added 114 μL (285 μmol) of 2.5 M solution of n BuLi in hexanes. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. To the mixture were added 2 mL of saturated NH 4 Cl, and the mixture was extracted with CH 2 Cl 2 (3 × 3 mL). The combined organics were dried with anhydrous Na 2 SO 4 and filtered, and the volatiles were removed in vacuo. The crude residue was purified by flash chromatography (5% EtOAc/DCM) to afford 94 mg (94%) of 19a as a colorless foam.